Obesity originates with the unbalance between energy intake and energy consumption, which has been considered as one of the major causes of health problems. Obesity is closely related to various pathological disorders such as hypertension, hyperlipidemia, arteriosclerosis, degenerative arthritis, type II diabetes, and coronary heart disease. The interaction of natural factors and genetic factors is also a cause of obesity. The treatment method of obesity is categorized according to their different mechanisms like the inhibition of lipase, the inhibition of energy intake, the stimulation of energy consumption, the inhibition of adipocyte differentiation, and the regulation of fat metabolism. A new strategy is recently applied to inhibit pancreatic lipase which is the major reason of excessive calorie to inhibit the absorption of neutral fat (triglyceride) included in food. Pancreatic lipase has been well known as a key enzyme to play an important role in neutral fat (triglyceride) absorption. This enzyme is secreted in pancreas and hydrolyzes neutral fat to glycerol and fatty acid. Orlistat, one of anti-obesity agents, is a potential pancreatic lipase inhibitor obtained naturally from Streptomyces Toxytricini, which is clinically utilized for the treatment of obesity by reducing energy intake during meal time. Obesity is defined by the increase in the number and size of adipocytes differentiated from 3T3-L1 preadipocytes. Therefore, the suppression of lipase, and the regulation of fat absorption and accumulation induced by adipocyte differentiation are considered as important factors for the development of anti-obesity agents.
Rotenoids belong to legumes, which have been well known as isoflavonoid generated in Derris, Lonchocarpus, and Tephrosia. These metabolites contain tetrahydrochromeno[3,4b] chromene ring core structure formed by modification of each member. Rotenoids have a wide variety of biological characteristics including potential anti-bacterial, anti-malaria, anti-cancer, and anti-microbial activity, etc. Recent reports proved that rotenone showed potential anti-cancer activity in some cancer cell lines by interacting with microtubules. The above founding opened the possibility for rotenone as an anti-cancer agent candidate, which is drawing our attention. Various attempts have also been made to provide novel and usable derivatives via structural change by chemical synthesis. In those studies, however, rotenone and its derivatives were unnoticed as starting materials for biotransformation. In the meantime, gamma-irradiation was proved in many previous studies to be an effective method to increase bioactivity and induce structural change of natural substances. However, it is still very limited in study of transformation of secondary metabolites having different natural basic structures by irradiation.
The present inventors studied and confirmed that the novel rotenone derivatives isolated and identified by gamma-irradiation had no cytotoxicity but had excellent pancreatic lipase inhibiting activity and adipocyte differentiation inhibiting activity, compared with the mother compound. Based on the above confirmation, the present inventors further completed this invention by proving that the novel rotenone derivatives, thereby, could be effectively used for the prevention and treatment of obesity.